The core aim of this project is to elucidate the nature, molecular foundations, underlying neurochemistry, and clinical correlates of neural systems-level dysfunction in schizophrenia. Toward that end, this year, the Clinical and Translational Neuroscience Branch has successfully executed comprehensive, multimodal positron emission and magnetic resonance based studies of a unique and steadily growing cohort of individuals with schizophrenia who have agreed to be studied under placebo (medication-free) conditions as well as matched healthy individuals. Though this work is necessarily challenging to conduct, we continue to make progress in data collection, which now includes characterization of dopamine-dependent mnemonic and reward-related neural responses, striatal presynaptic dopamine synthetic capacity, and both D1 and D2/3 receptor availability, as well as prefrontal measurements of GABA and glutamate concentrations. In order to develop precision, personalized clinical care in the treatment of schizophrenia, greater neurobiological understanding is needed of the high variability across individuals in medication response. This past year, in efforts to address this knowledge gap, we have focused our work on identifying not only important alterations in neural systems with medication, but also the neurochemical predictors of neuroleptic-driven changes in brain activity and symptom burden. For instance, using MRS, we have found that antipsychotic medications tend to increase the amount of the inhibitory neurotransmitter, GABA, in the anterior cingulate cortex (ACC). However, GABA levels did not appear to be predictive of symptom change. On the other hand, preliminary data suggest that levels of the excitatory neurotransmitter, glutamate, in the same brain region are negatively associated with antipsychotic response, such that patients with high cortical glutamate might derive less benefit from currently available drugs with dopaminergic mechanisms. To better understand the relevance of these findings to neural function, we have also investigated the relationship between MRS-measured metabolite levels and fMRI-measured blood oxygen level-dependent (BOLD) signal during a behavioral inhibition task. We found that while GABA levels in the dorsal anterior cingulate cortex (dACC) are poorly predictive of fMRI activation, glutamate levels are predictive of activation in regions of the prefrontal cortex that are functionally connected to the dACC and that are important for the execution of the task. Furthermore, glutamate levels are positively correlated with BOLD activation in controls, but they are negatively correlated in patients with schizophrenia. Altogether, these data indicate a dysregulation of glutamate metabolism in patients with schizophrenia with likely consequences for functional activation and behavioral performance. Further work has been focused on subcortical neural systems in schizophrenia, where we have employed positron emission tomography methods to understand the functional and neurochemical consequences of antipsychotic treatment. After identification of striatal blood flow enhancement in medicated states, which may predict aspects of concurrent symptom change, we have employed 18FFDOPA PET to characterize relationships between striatal dopaminergic synthetic tone and co-localized neural activity changes with antipsychotic treatment under the hypothesis that variability in striatal blood flow response might be due in part to trait differences in dopaminergic tone. Finally, we have completed recruitment in two personalized-medicine drug trials examining interactions between genotype for COMT, an enzyme important for maintaining cortical dopamine, and effects of dopamine-modulating medication on cognitive function in schizophrenia. Analyses of data is ongoing in order to understand how these integrative, multimodal clinical data might bridge an important gap between pharmacotherapeutics, neurophysiology and neurochemistry. This work involves the following studies: NCT00942981, NCT00001258, NCT00024622, NCT00004571, NCT00001247, NCT00044083, NCT00057707